Affinity labels (ALs) for receptors would serve as powerful pharmacologic probes for studying receptor structure and function and as potential clinical agents with unusual activity profiles. For several receptor systems, there is good evidence for the existence and possible whereabouts of recognition-site nucleophiles which can serve as targets for a rational design of receptor ALs. A special significance for receptor ALs is in regard to the recently realized phenomena of subpopulation diversity within most neurotransmitter systems. In cases where the distinction among these multiple subpopulations is not achievable with the utilization of conventional reversible ligands, ALs bearing selective electrophilic moieties might be successful in this regard by virtue of their ability to discriminate on the basis of covalent rather than non-covalent bonding. The multiple opioid receptor system is a particularly attractive candidate for applying an affinity labeling strategy, where there is an urgent need to correlate the involvement of individual receptor subpopulations with the increasingly appreciated pervasive role of this system in modulating neurotransmitter and hormonal action in the brain and periphery, including implications in several disease states and other physiologic and behavioral aberrations. This proposal involves a two-part program, the first of which is to develop an armamentarium of selective AL moieties which can be conveniently incorporated into classical receptor ligands in an effort to achieve different contingencies of affinity labeling. Studies will demonstrate mild methods for such incorporation, and will examine the potential reactivity of model ALs with biologically relevant nucleophiles. The second part of the program will be to apply the strategies developed to the preparation of potential opioid receptor ALs from amenable small-molecule high-affinity ligands. Such small molecules are believed to best represent the minimum structural requirements for receptor recognition, and should thus serve as optimum substrates for the development of selective ALs for each of the hypothetical receptor subpopulations. Pharmacologica evaluation of these latter agents will be conducted by collaborators during the normal course of their research.